tbuckley/cabot-search huggingface dataset:
N6-methyladenosine-modified circRIMS2 mediates synaptic and memory impairments by activating GluN2B ubiquitination in Alzheimer's disease
Authors: Xiong Wang, Jiazhao Xie, Lu Tan, Yanjun Lu, Na Shen, Jiaoyuan Li, Hui Hu, Huijun Li, Xiaoguang Li, Liming Cheng
Journal: Translational Neurodegeneration (2023)

Abstract Background Synaptic degeneration occurs in the early stage of Alzheimer's disease (AD) before devastating symptoms, strongly correlated with cognitive decline. Circular RNAs (circRNAs) are abundantly enriched in neural tissues, and aberrant expression of circRNAs precedes AD symptoms, significantly correlated with clinical dementia severity. However, the direct relationship between circRNA dysregulation and synaptic impairment in the early stage of AD remains poorly understood. Methods Hippocampal whole-transcriptome sequencing was performed to identify dysregulated circRNAs and miRNAs in 4-month-old wild-type and APP/PS1 mice. RNA antisense purification and mass spectrometry were utilized to unveil interactions between circRIMS2 and methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit (METTL3). The roles of circRIMS2/miR-3968 in synaptic targeting of UBE2K-mediated ubiquitination of GluN2B subunit of NMDA receptor were evaluated via numerous lentiviruses followed by morphological staining, co-immunoprecipitation and behavioral testing. Further, a membrane-permeable peptide was used to block the ubiquitination of K1082 on GluN2B in AD mice. Results circRIMS2 was significantly upregulated in 4-month-old APP/PS1 mice, which was mediated by METTL3-dependent N6-methyladenosine (m6A) modification. Overexpression of circRIMS2 led to synaptic and memory impairments in 4-month-old C57BL/6 mice. MiR-3968/UBE2K was validated as the downstream of circRIMS2. Elevated UBE2K induced synaptic dysfunction of AD through ubiquitinating K1082 on GluN2B. Silencing METTL3 or blocking the ubiquitination of K1082 on GluN2B with a short membrane-permeable peptide remarkably rescued synaptic dysfunction in AD mice. Conclusions In conclusion, our study demonstrated that m6A-modified circRIMS2 mediates the synaptic and memory impairments in AD by activating the UBE2K-dependent ubiquitination and degradation of GluN2B via sponging miR-3968, providing novel therapeutic strategies for AD.
LncRNA‐CCAT5‐mediated crosstalk between Wnt/β‐Catenin and STAT3 signaling suggests novel therapeutic approaches for metastatic gastric cancer with high Wnt activity
Authors: Chenchen Liu, Aiwen Shen, Junquan Song, Lei Cheng, Meng Zhang, Yanong Wang, Xiaowen Liu
Journal: Cancer Communications (2023)

Abstract Background Although the constitutively activated Wnt/β‐catenin signaling pathway plays vital roles in gastric cancer (GC) progression, few Wnt inhibitors are approved for clinical use. Additionally, the clinical significance of long non‐coding RNAs (lncRNAs) in GC intraperitoneal dissemination (IPD) remains elusive. Here, we investigated the function and therapeutic potential of Wnt‐transactivated lncRNA, colon cancer‐associated transcript 5 (CCAT5), in GC metastasis. Methods LncRNA‐sequencing assay was performed to document abundance changes of lncRNAs induced by Wnt family member 3A (Wnt3a) and degradation‐resistant β‐catenin (S33Y mutated) in ascites‐derived GC cells with low Wnt activity. Luciferase reporter, Chromatin immunoprecipitation (ChIP)‐re‐ChIP assays were performed to determine how CCAT5 was transcribed. The clinical significance of CCAT5 was examined in 2 cohorts of GC patients. The biological function of CCAT5 was investigated through gain‐ and loss‐of‐function studies. The molecular mechanism was explored through RNA‐sequencing, mass spectrometry, and CRISPR/Cas9‐knocknout system. The therapeutic potential of CCAT5 was examined through RNAi‐based cell xenograft model and patient‐derived xenograft (PDX) model of IPD. Results We identified a novel Wnt‐regulated lncRNA, CCAT5, which was transactivated by the β‐catenin/transcription factor 3 (TCF3) complex. CCAT5 was significantly upregulated in GC and predicted poor prognosis. Functional studies confirmed the promotive role of CCAT5 in GC growth and metastasis. Mechanistically, CCAT5 bound to the C‐end domain of signal transducer and activator of transcription 3 (STAT3) and blocks Src homology 2 domain‐containing protein tyrosine phosphatase 1 (SHP‐1)‐mediated STAT3 Y705 dephosphorylation, leading to STAT3 nuclear entry and transactivation, thus accelerating GC progression. Furthermore, we demonstrated that both Wnt3a and β‐catenin acted as activator of STAT3 signaling pathway, and the interplay between CCAT5 and STAT3 was functionally essential for Wnt‐drived STAT3 signaling and tumor evolution. Finally, we revealed in vivo si‐CCAT5 selectively attenuated growth and metastasis of Wnt high GC, but not Wnt low GC. The combination of si‐CCAT5 and oxaliplatin displayed obvious synergistic therapeutic effects on Wnt high PDX mice. Conclusions We identified a novel Wnt‐transactivated lncRNA, CCAT5. Our study revealed a mechanism of STAT3 signaling regulation via canonical Wnt signaling and the functional significance of CCAT5 as critical mediator. We provided conceptual advance that lncRNAs serve as therapeutic targets reversing GC progression.
Patient‐Derived Microphysiological Systems for Precision Medicine
Authors: Jihoon Ko, Jiyoung Song, Nakwon Choi, Hong Nam Kim
Journal: Advanced Healthcare Materials (2023)

Patient-derived microphysiological systems (P-MPS) have emerged as powerful tools in precision medicine that provide valuable insight into individual patient characteristics. This review discusses the development of P-MPS as an integration of patient-derived samples, including patient-derived cells, organoids, and induced pluripotent stem cells, into well-defined MPSs. Emphasizing the necessity of P-MPS development, its significance as a nonclinical assessment approach that bridges the gap between traditional in vitro models and clinical outcomes is highlighted. Additionally, guidance is provided for engineering approaches to develop microfluidic devices and high-content analysis for P-MPSs, enabling high biological relevance and high-throughput experimentation. The practical implications of the P-MPS are further examined by exploring the clinically relevant outcomes obtained from various types of patient-derived samples. The construction and analysis of these diverse samples within the P-MPS have resulted in physiologically relevant data, paving the way for the development of personalized treatment strategies. This study describes the significance of the P-MPS in precision medicine, as well as its unique capacity to offer valuable insights into individual patient characteristics.
Safety and immunopharmacology of ASP0892 in adults or adolescents with peanut allergy: two randomized trials
Authors: Brian C. Ferslew, Ronald Smulders, Tong Zhu, Mary B. Blauwet, Tomohiro Kusawake, Anna Spence, Kelly Aldridge, Hannah A. DeBerg, Sugandhika Khosa, Erik Wambre, Gurunadh R. Chichili
Journal: Allergy (2023)

Abstract Background New treatment options with improved safety and novel mechanisms of actions are needed for patients with peanut allergy. Objectives To evaluate the safety, tolerability, and immunogenicity of ASP0892, a peanut DNA vaccine, after intradermal (id) or intramuscular (im) administration in adult or adolescent patients with peanut allergy in two phase 1 studies. Methods ASP0892 or placebo was administered every 2 weeks for a total of 4 doses. The doses were 1 mg or 4 mg id or 4 mg im for adults, and 1 mg or 4 mg id for adolescents. Immunologic parameters were assessed longitudinally. Results Thirty‐one adults (mean age 24.3 years, 17 males) received ASP0892 (9, 8, 8 patients for 1 mg id, 4 mg id or 4 mg im, respectively) or placebo (2 patients/group). Twenty adolescents (mean age 14.2 years, 11 males) received ASP0892 (8 patients/group) or placebo (2 patients/group). In both studies, the most common treatment‐emergent adverse event (TEAE) was injection site pruritus. No deaths or treatment withdrawal were related to TEAEs. No serious TEAEs related to treatment were observed in adult or adolescent patients. ASP0892 treatment led to modest increases in allergen‐specific IgG and/or IgG4 in adults (1 mg id, 4 mg im) and adolescents (1 mg id, 4 mg id). No improvements in clinical outcomes, including double‐blind placebo‐controlled food challenge, were found after ASP0892 treatment. Conclusions In two phase 1 studies, ASP0892 was well tolerated with modest but not clinically relevant changes in immune responses. ClinicalTrials.gov Identifiers NCT02851277, NCT03755713.
Implementation of a high sensitivity cardiac troponin I assay and risk of myocardial infarction or death at five years: observational analysis of a stepped wedge, cluster randomised controlled trial
Authors: Kuan Ken Lee, Dimitrios Doudesis, Amy V Ferry, Andrew R Chapman, Dorien M Kimenai, Takeshi Fujisawa, Anda Bularga, Matthew T H Lowry, Caelan Taggart, Stacey Schulberg, Ryan Wereski, Chris Tuck, Fiona E Strachan, David E Newby, Atul Anand, Anoop S V Shah, Nicholas L Mills
Journal: BMJ (2023)

Abstract Objective To evaluate the impact of implementing a high sensitivity assay for cardiac troponin I on long term outcomes in patients with suspected acute coronary syndrome. Design Secondary observational analysis of a stepped wedge, cluster randomised controlled trial. Setting 10 secondary and tertiary care centres in Scotland, UK. Participants 48 282 consecutive patients with suspected acute coronary syndrome. Myocardial injury was defined as any high sensitivity assay result for cardiac troponin I &gt;99th centile of 16 ng/L in women and 34 ng/L in men. Intervention Hospital sites were randomly allocated to either early (n=5 hospitals) or late (n=5 hospitals) implementation of a high sensitivity cardiac troponin I assay with sex specific diagnostic thresholds. Main outcome measure The main outcome was myocardial infarction or death at five years. Results 10 360 patients had cardiac troponin concentrations greater than the 99th centile, of whom 1771 (17.1%) were reclassified by the high sensitivity assay. The five year incidence of subsequent myocardial infarction or death before and after implementation of the high sensitivity assay was 29.4% (5588/18 978) v 25.9% (7591/29 304), respectively, in all patients (adjusted hazard ratio 0.97, 95% confidence interval 0.93 to 1.01), and 63.0% (456/720) v 53.9% (567/1051), respectively, in those reclassified by the high sensitivity assay (0.82, 0.72 to 0.94). After implementation of the high sensitivity assay, a reduction in subsequent myocardial infarction or death was observed in patients with non-ischaemic myocardial injury (0.83, 0.75 to 0.91) but not in those with type 1 or type 2 myocardial infarction (0.92, 0.83 to 1.01 and 0.98, 0.84 to 1.14). Conclusions Implementation of a high sensitivity cardiac troponin I assay in the assessment of patients with suspected acute coronary syndrome was associated with a reduced risk of subsequent myocardial infarction or death at five years in those reclassified by the high sensitivity assay. Improvements in outcome were greatest in patients with non-ischaemic myocardial injury, suggesting a broader benefit beyond the identification of myocardial infarction. Trial registration ClinicalTrials.gov NCT01852123 .
Defining curative endpoints for sickle cell disease in the era of gene therapy and gene editing
Authors: Franco Locatelli, Selim Corbacioglu, William Hobbs, Haydar Frangoul, Mark C. Walters
Journal: American Journal of Hematology (2023)

Abstract A growing number of gene therapy‐ and gene editing‐based treatments for patients with sickle cell disease (SCD) are entering clinical trials. These treatments, designed to target the underlying cause of SCD, have the potential to provide functional cures, which until now were possible only through allogeneic hematopoietic stem cell transplant. However, as these novel approaches advance from early‐ to late‐stage clinical trials, it is essential to identify physiologically and clinically relevant endpoints that can demonstrate the achievement of a functional cure for SCD. Here, we present an overview of the pathophysiology of SCD and current treatment options, review ongoing SCD clinical trials using gene therapy or gene editing approaches, and identify the most relevant endpoints for demonstrating the attainment of a functional cure for SCD.
Polyelectrolyte Complex Hydrogels from Controlled Kneading and Annealing‐Induced Tightly Wound and Highly Entangled Natural Polysaccharides
Authors: Shunlan Chen, Dapeng Li, Ying Wen, Gege Peng, Kexin Ye, Yiwan Huang, Shijun Long, Xuefeng Li
Journal: Advanced Healthcare Materials (2023)

Abstract Hydrogels usually are fabricated by using monomers or preexisting polymers in precursor solutions. Here, a polyelectrolyte complex biohydrogel (Bio‐PEC hydrogel) made from a precursor dough, by kneading, annealing, and crosslinking the dough of two oppositely charged polysaccharides, cationic chitosan quaternary ammonium salt (HACC) and anionic sodium hyaluronate (HA), photoinitiator (α‐ketoglutaric acid), crosslinker glycidyl methacrylate (GMA), and water of very small quantity is reported. Controlled kneading and annealing homogenized the dough with respect to transforming randomly distributed, individual polymer chains into tightly wound double‐stranded structures, which, upon UV irradiation, covalently sparsely crosslinked into a highly entangled network and subsequently, upon fully swollen in water, results in Bio‐PEC hydrogel, HACC/HA, exhibiting near‐perfect elasticity, high tensile strength, and high swelling resistance. Via the same kneading and annealing, tetracarboxyphenylporphyrin iron (Fe‐TCPP) metal nanoclusters are incorporated into HACC/HA to obtain photocatalytic, antibacterial, and biocompatible Bio‐PEC hydrogel composite, Fe‐TCPP@HACC/HA. Using SD rat models, the efficacy of Fe‐TCPP@HACC/HA in inhibiting Escherichia coli ( E. coli ) growth in vitro and the ability to promote wound healing and scar‐free skin regeneration in vivo, or its high potential as a wound dressing material for biomedical applications are demonstrated.
B Cell–Directed Therapy in Autoimmunity
Authors: Ilana Abeles, Chris Palma, Nida Meednu, Aimee S. Payne, R. John Looney, Jennifer H. Anolik
Journal: Annual Review of Immunology (2023)

Autoimmune diseases with B cell–directed therapeutics approved by the US Food and Drug Administration are surprisingly diverse in clinical manifestations and pathophysiology. In this review, we focus on recent clinical and mechanistic insights into the efficacy of B cell depletion in these diverse autoimmune disorders, the rapidly expanding armamentarium of approved agents, and future approaches. The pathogenic roles for B cells include direct functions such as production of autoantibodies and proinflammatory cytokines and indirect functions via antigen presentation to T cells. The efficacy of B cell–depleting strategies varies across diseases and likely reflects the complexity of disease pathogenesis and relative contribution of B cell roles. Additionally, B cell–depleting therapies do not equally target all B cell subsets in all patients, and this likely explains some of the variability in responses. Recent reports of B cell depletion with novel chimeric antigen receptor (CAR) T cell approaches in an expanding number of autoimmune diseases highlight the potential role of B cell depletion in resetting immune tolerance. The relative importance of eliminating autoreactive B cells and plasma cells and approaches to doing so will also be discussed. Expected final online publication date for the Annual Review of Immunology, Volume 42 is April 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Bioactives and Biomaterial Construction for Modulating Osteoclast Activities
Authors: Yuwei He, Hong Jiang, Shiwu Dong
Journal: Advanced Healthcare Materials (2023)

Abstract Bone tissue constitutes 15–20% of human body weight and plays a crucial role in supporting the body, coordinating movement, regulating mineral homeostasis, and hematopoiesis. The maintenance of bone homeostasis relies on a delicate balance between osteoblasts and osteoclasts. Osteoclasts, as the exclusive “bone resorbers” in the human skeletal system, are of paramount significance yet often receive inadequate attention. When osteoclast activity becomes excessive, it frequently leads to various bone metabolic disorders, subsequently resulting in secondary bone injuries, such as fractures. This not only reduces life quality of patients, but also imposes a significant economic burden on society. In response to the pressing need for biomaterials in the treatment of osteoclast dysregulation, there is a surge of research and investigations aimed at osteoclast regulation. Promising progress is achieved in this domain. This review seeks to provide a comprehensive understanding of how to modulate osteoclast activities. It summarizes bioactive substances that influence osteoclasts and elucidates strategies for constructing related biomaterial systems. It offers practical insights and ideas for the development and application of biomaterials and tissue engineering, with the hope of guiding the clinical treatment of osteoclast‐related bone diseases using biomaterials in the future.
Biomimetic Structure Hydrogel Loaded with Long‐Term Storage Platelet‐Rich Plasma in Diabetic Wound Repair
Authors: Neng Ding, Xinxin Fu, Qixiang Gui, Minjuan Wu, Zhongpu Niu, Antong Du, Jinyue Liu, Haimei Wu, Yue Wang, Xuezheng Yue, Lie Zhu
Journal: Advanced Healthcare Materials (2023)

Exploring the preparation of multifunctional hydrogels from a bionic perspective is an appealing strategy. Here, a multifunctional hydrogel dressing inspired by the characteristics of porous extracellular matrix produced during Acomys wound healing is prepared. These dressings are printed by digital light processing printing of hydrogels composed of gelatin methacrylate, hyaluronic acid methacrylate, and pretreated platelet-rich plasma (PRP) to shape out triply periodic minimal surface structures, which are freeze-dried for long-term storage. These dressings mimic the porous extracellular matrix of Acomys, while the freeze-drying technique effectively extends the storage duration of PRP viability. Through in vivo and in vitro experiments, the biomimetic dressings developed in this study modulate cell behavior and facilitate wound healing. Consequently, this research offers a novel approach for the advancement of regenerative wound dressings.
Using Polygenic Risk Scores to Aid Diagnosis of Patients With Early Inflammatory Arthritis: Results From the Norfolk Arthritis Register
Authors: Ryan M. Hum, Seema D. Sharma, Michael Stadler, Sebastien Viatte, Pauline Ho, Nisha Nair, Chenfu Shi, Chuan Fu Yap, Mehreen Soomro, Darren Plant, Jenny H. Humphreys, Alexander MacGregor, Max Yates, Suzanne Verstappen, Anne Barton, John Bowes
Journal: Arthritis & Rheumatology (2023)

Objective There is growing evidence that genetic data are of benefit in the rheumatology outpatient setting by aiding early diagnosis. A genetic probability tool (G‐PROB) has been developed to aid diagnosis has not yet been tested in a real‐world setting. Our aim was to assess whether G‐PROB could aid diagnosis in the rheumatology outpatient setting using data from the Norfolk Arthritis Register (NOAR), a prospective observational cohort of patients presenting with early inflammatory arthritis. Methods Genotypes and clinician diagnoses were obtained from patients from NOAR. Six G‐probabilities (0%–100%) were created for each patient based on known disease‐associated odds ratios of published genetic risk variants, each corresponding to one disease of rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, spondyloarthropathy, gout, or “other diseases.” Performance of the G‐probabilities compared with clinician diagnosis was assessed. Results We tested G‐PROB on 1,047 patients. Calibration of G‐probabilities with clinician diagnosis was high, with regression coefficients of 1.047, where 1.00 is ideal. G‐probabilities discriminated clinician diagnosis with pooled areas under the curve (95% confidence interval) of 0.85 (0.84–0.86). G‐probabilities &lt;5% corresponded to a negative predictive value of 96.0%, for which it was possible to suggest &gt;2 unlikely diseases for 94% of patients and &gt;3 for 53.7% of patients. G‐probabilities &gt;50% corresponded to a positive predictive value of 70.4%. In 55.7% of patients, the disease with the highest G‐probability corresponded to clinician diagnosis. Conclusion G‐PROB converts complex genetic information into meaningful and interpretable conditional probabilities, which may be especially helpful at eliminating unlikely diagnoses in the rheumatology outpatient setting. image
N‐Heterocycle Modified Graphene Quantum Dots as Topoisomerase Targeted Nanoantibiotics for Combating Microbial Infections
Authors: Yan Su, Jinyan Hu, Yang Wang, Yuan Li, Longfei Xiao, Xialing He, Zhenlin Zhang, Jinming Cai, Dengyu Pan, Yu Chen, Bijiang Geng, Ping Li, Longxiang Shen
Journal: Advanced Healthcare Materials (2023)

Abstract Developing next‐generation antibiotics to eliminate multidrug‐resistant (MDR) bacteria/fungi and stubborn biofilms is challenging, because of the excessive use of currently available antibiotics. Herein, the fabrication of anti‐infection graphene quantum dots (GQDs) is reported, as a new class of topoisomerase (Topo) targeting nanoantibiotics, by modification of rich N‐heterocycles (pyridinic N) at edge sites. The membrane‐penetrating, nucleus‐localizing, DNA‐binding GQDs not only damage the cell walls/membranes of bacteria or fungi, but also inhibit DNA‐binding proteins, such as Topo I, thereby affecting DNA replication, transcription, and recombination. The obtained GQDs exhibit excellent broad‐spectrum antimicrobial activity against non‐MDR bacteria, MDR bacteria, endospores, and fungi. Beyond combating planktonic microorganisms, GQDs inhibit the formation of biofilms and can kill live bacteria inside biofilms. RNA‐seq further demonstrates the upregulation of riboflavin biosynthesis genes, DNA repair related genes, and transport proteins related genes in methicillin‐resistant S. aureus (MRSA) in response to the stress induced by GQDs. In vivo animal experiments indicate that the biocompatible GQDs promote wound healing in MRSA or C. albicans ‐infected skin wound models. Thus, GQDs may be a promising antibacterial and antifungal candidate for clinical applications in treating infected wounds and eliminating already‐formed biofilms.